5‐hydroxyindole causes convulsions and increases transmitter release in the CA1 region of the rat hippocampus

Abstract

1 5-hydroxyindole (5-OHi) is a proposed tryptophan metabolite able to cause convulsions when systemically injected into rodents. We studied its e ects using microdialysis in vivo and electrophysiological approaches in vitro. 2 Local administration of 5-OHi into the CA1 region of the rat hippocampus, via a microdialysis probe, signi®cantly increased glutamate concentrations in the dialysates. 3 In rat hippocampal slices, using extracellular recordings in the CA1 region, 5-OHi (30 ± 300 mM) increased the amplitude of population spikes and fEPSPs. 4 In the same preparation, using intracellular recordings in CA1 pyramidal neurons, 5-OHi reduced the latency of ®ring induced by direct depolarization and increased both evoked excitatory and slow inhibitory postsynaptic potential amplitudes, without a ecting the resting membrane potential, the after-hyperpolarization or the neuronal input resistance. It also altered GABA Amediated neurotransmission by increasing the frequency and the amplitude of pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSC). 5 In separate experiments, performed by measuring AMPA or NMDA-induced depolarization in cortical wedges, 5-OHi did not modify glutamate receptor agonist responses. 6 Our results show that 5-OHi causes convulsions, modi®es the properties and the function of the hippocampal circuitry, and facilitates the output of both excitatory and inhibitory transmitters.

Modulation of spontaneous hippocampal synaptic events with 5-hydroxyindole, 4OH-GTS-21, and rAAV-mediated α7 nicotinic receptor gene transfer

“…Since the 5HI + 4OH-GTS-21 mediated increase in EPSC frequency was blocked with TTX but unchanged by MLA, our data suggest these effects were not mediated by direct activation of α7 nAChRs, but rather by increases in action potential-dependent transmitter release. This is consistent with studies that have shown 5-HI mediated increases in glutamate release, the amplitude of population spikes, and the amplitude of evoked excitatory postsynaptic potentials in the hippocampus (Mannaioni et al, 2003). However, to our knowledge, this is the first report showing that 5-HI potentiates the frequency of spontaneous EPSCs in CA1 pyramidal cells.…”

“…However, 5-HI also produces a number of other physiological effects. For example, in the hippocampus 5-HI increases glutamate release, the amplitude of population spikes, and the amplitude of evoked excitatory and inhibitory postsynaptic potentials (Mannaioni et al, 2003). Also, 5-HI increases the frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) (Mannaioni et al, 2003;Mok and Kew, 2006).…”

“…For example, in the hippocampus 5-HI increases glutamate release, the amplitude of population spikes, and the amplitude of evoked excitatory and inhibitory postsynaptic potentials (Mannaioni et al, 2003). Also, 5-HI increases the frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) (Mannaioni et al, 2003;Mok and Kew, 2006). Thus, 5-HI is an effective positive allosteric modulator of α7 nAChRs that facilitates the output of both excitatory and inhibitory neurotransmission, although it is unclear from previous studies if all of the effects reported for 5-HI arise strictly from the positive modulation of α7 nAChRs.…”

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

“…The 5-HT 3 receptor is not only the target of the natural agonist 5-HT but also a variety of allosteric modulators including the 5-HT analog 5-hydroxyindole (5-HI). Both 5-HT and 5-HI are metabolites of tryptophan (Mannaioni et al, 2003). 5-HI has been shown to increase release of neurotransmitter in the cerebellum and hippocampus (Zwart et al, 2002;Mannaioni et al, 2003) and triggers convulsion in rats (Mannaioni et al, 2003).…”

“…Both 5-HT and 5-HI are metabolites of tryptophan (Mannaioni et al, 2003). 5-HI has been shown to increase release of neurotransmitter in the cerebellum and hippocampus (Zwart et al, 2002;Mannaioni et al, 2003) and triggers convulsion in rats (Mannaioni et al, 2003). 5-HI is a positive modulator of the 5-HT 3 receptor (Kooyman et al, 1993;van Hooft et al, 1997;Gunthorpe & Lummis, 1999) and α7 nicotinic acetylcholine receptor (Zwart et al, 2002;Selina Mok & Kew, 2006).…”